The present invention relates to biomimetic iron carriers useful for iron removal from mammalian cells and from pathogenic organisms infecting mammals, including humans.
Iron is an essential metal for the growth of all organisms as it participates in several vital processes such as oxygen metabolism and electron transfer reactions, nucleic acid synthesis and a variety of enzyme catalysis. Microorganisms, primarily the bacteria and fungi, obtain iron from their environment by secretion of low molecular weight siderophores that bind iron (III) at high affinity (K.sub.a &gt;10.sup.30) and return to the cell surface where iron delivery occurs via receptor mediated uptake.
Iron (III) chelators are important as therapeutic tools for the treatment of iron overload and of infectious diseases caused by iron-dependent pathogens, such as malaria caused by Plasmodium falciparum (Dionis, J. B. et al., 1991 CRC Handbook of Microbial Iron Chelates (ed. by G. Winkelmann), pp. 309-338. Early efforts to improve the performance of iron chelation agents in medicine have been directed at synthesis of analogs of enterobactin family which display high affinity for iron (III) and mobilize iron from ferric proteins (Kontoghiorghes, G. J. and Evans, R. W., 1985, FEBS Lett., 189:141-144; Kontoghiorghes, G. J., 1986 Biochem. J. 233:299-302; Kretchmar, S. A. and Raymond, K. N., 1986, Am. Chem. Soc. 108:6212-6218; Tufano, T. P. et al., 1981, Biochim. et Biophys. Acta 668:420-428). These agents have limitations for use in vivo due to their restricted membrane permeation properties (Shanzer, A. and Libman, J., 1991 CRC Handbook of Microbial Iron Chelates (ed. by G. Winkelmann) pp. 309-338) and their propensity to remove iron (III) from both ferritins and transferrin (Tufano, T. P. et al., 1981, Biochim. et Biophys. Acta 668:420-428; Hider, R. C. 1984, Struct. and Bond 5:25-84). On the other hand, the use of the natural siderophore, desferrioxamine B (DFO), in iron chelation therapy has scored a wide success, mainly due to the capacity of the hydroxamates to chelate iron from ferritin and the relatively slow scavenging of iron from transferrin. However, DFO has to be administered by infusion and causes several side effects (Porter, J. 1989, Eur. J. Haematol. 43:271-285).
Previous attempts to employ synthetic iron binders as in vitro and in vivo growth inhibitors of intraerythrocytic parasites scored some success (Scheibel, L. W. and Adler, A. (1981) Mol. Pharmacol. 20: 218-223, and 22: 140-144; Scheibel, L. W. and Stanton, G. G. (1986) Mol. Pharmacol. 30: 364-369; Scheibel, L. W. and Rodriguez, S. (1989) in Malaria and the red cell, Alan R. Liss Inc. 2: 119-149; Heppner, D. G., et al., (1988) Blood 72: 358-361; Raventos-Suarez, C., et al. (1982) Am. J. Trop. Med. Hyg. 31: (5), 919-922; Stahel, E., et al. (1988) Am. J. Trop. Med. Hyg. 39: 236-240; Pollack, S. (1983) British J. Haematol, 53: 181-183). However, each class of compounds thus far examined has shown some drawbacks. Synthetic dithiocarbamates and hydroxyquinolines proved efficacious, because of their high permeation features, but the fact that their antimalarial potency depends on their forming cytotoxic metal complexes has seriously curtailed their use (Scheibel, L. W. and Rodriguez, S. (1989) in Malaria and the red cell, Alan R. Liss Inc. 2: 119-149). Synthetic, lipophilic catecholates which acted as specific iron scavengers and showed satisfactory membrane penetration, appeared also of limited use because they demonstrably deplete serum iron pools (Heppner, D. G., et al., (1988) Blood 72: 358-361).
The present invention relates to iron (III) carriers which are designed to overcome the above limitations and to show: (1) high selectivity for iron; (2) permeation across cellular membranes including infected erythrocytes; (3) metabolic resistance by being built from enantiomers of natural amino acids; (4) lack of growth promotion activity towards pathogenic organisms by not binding to siderophore receptors present in said organisms, and (5) lack of side effects leading to anemic conditions by not sequestering iron from transferrin, the mammalian iron carrier.